Novel 7-thioacyl-17-spirolactone gonanes



United States Patent 3,452,008 NOVEL 7-THIOACYL-17-SPIROLACTONE GONANES George C. Buzby, Jr., Philadelphia, and Herchel Smith, Wayne, Pa., assignors to American Home Products C0r poration, New York, N.Y., a corporation of Delaware No Drawing. Filed Aug. 12, 1966, Ser. No. 572,002

Int. Cl. C07c 173/00; A61k 17/06 U.S. Cl. 260-23957 5 Claims ABSTRACT OF THE DISCLOSURE This invention concerns new and novel 13-alkyl-l7- hydroxy-7a-mercapto-3-oxogon-4-ene-17a-propionic acid, 'y-lactone, acylates which are pharmacologically active as anti-diuretic agents.

This invention relates to new and novel 7-thioacyl-17- spirolactone gonanes and related intermediate compounds.

Aeylation and wherein R is alkyl containing from two to six carbon atoms and R is lower alkyl. The new compounds of the above Formula A are properly called: 13-a1ky1-17- hydroxy-3-oxogona-4,6-diene-17a-propionic acid, 'y-lac tones. Typical examples thereof are: 13-ethyl-17- hydroxy-3-oxogona-4,6-diene-17a-propionic acid, 2-lactone; 13 butyl-l7-hydroxy-3-oxogona-4,6-diene-l7u-propicnic acid, 'y-lactone; and 17-hydroxy-3-oxogona-4,6- diene-l3-propyl-17a-propionic acid, 'y-lactone. The new compounds of the above Formula B are properly designated: 13 alkyl 17-hydroxy-7a-mercapto-3-oxogon-4- ene-17a-propionic acid, -lactone, acylates, such as: 13-ethyl-17-hydroxy-7a-mercapto-3-oxogon-4 -ene 17apropionic acid, 'y-lactone, acetate; 13-buty1-17-hydroxy- 7u-propionic acid, 'y-lactone, propionate and-13-hexyl-17- hydroxy-7u-mercapto-3-oxogona-4 ene 17d propionic acid, 'y-lactone, butyrate.

The new and novel compounds of the present invention may be prepared by the process generally illustrated by the following equation:

1 J R J Halogenatlon m genation (II) (A) Condensation l wherein R and R are defined as above and R is lower alkyl. The 'acylation reaction is effected by contacting an acylating agent with a 13-alkyl-17-hydroxy-3-oxogon-4- ene-17a-propi0nic acid, 'y-lactone (I) and refluxing the mixture for from about a half hour to about five hours. Suitably this acylation may be conducted by contact with acetyl chloride, pyridine and acetic anhydride while other satisfactory acylating agents for this purpose will readily suggest themselves to those skilled in the chemical art. After the reaction is complete, the reaction mixture is evaporated to dryness, triturated with an alkanol and filtered to yield a 13-alkyl-3,17-dihydroxygona-3,5-diene- 17ix-propionic acid, 'y-lactone, acylate (H).

Halogenation and dehydrohalogenation of the above prepared 13-alkyl-3, 17-dihydroxygona-3, 5-diene-17a-propionic acid, 'y-lactone, acylate (H) is effected by admixing an aqueous mixture containing acetone, pyridine, sodium acetate, acetic acid and an appropriate compound (II) with a halogenating agent, such as, N-bromosuccinimide, and stirring the resulting mixture at a temperature from about 10 C. to about 10 C. for a period of about one to about four hours. Thereafter, the reaction mixture is poured into a salt solution; extracted with a water-immiscible organic solvent, e.g., ether, chloroform, carbon tetrachloride and hexane; and partially evaporated at re duced pressures and temperatures. The concentrate is then admixed with calcium carbonate and dimethylformamide. The mixture is then refluxed for a period of from one to three hours. After the dehydrohalogenation reaction is complete, the resulting 13-alkyl-l7-hydroxy-3-oxogona-4, 6-diene l7a-propionic acid, q-lactone (A) is obtained by conventional methods such as filtration, extraction and crystallation.

The condensation of a 13-alkyl-17-hydroxy-3-oxog0na 4,6-diene-17a-propionic acid, 'y-lactone (A) with a thiol carboxylic acid is eifected by refluxing a mixture thereof for a period of about one to about four hours. When the reaction is complete, the excess acid is removed by evaporation and the residue is the appropriate 13-alltyl-17- hydroxy-h-mercapto-S-oxogon-4-ene17a-propionic acid, y-lactone, acylate (B) which may be further purified by procedures well known to those skilled in the art of chemistry, such as, for example, trituration with ethyl acetate and filtration.

The starting steroids, the 13-alkyl-l7-hydroxy-3-oxogon-4-ene-17a-propionic acid, -lactones (I), utilized in the preparation of the compounds of this invention are prepared by the procedure described in copending United States patent application, Ser. No. 388,820, entitled Gon- 4-Enes, filed Aug. 11, 1 964 by Gordon Alan Hughes and Herchel Smith. The 13-alkyl-3,17-dihydroxygona-3,5-diene-l7ot-propionic acid, 'y-lactone, acylates (II) intermediates are known compounds which are described in United States patent application, Ser. No. 540,984, entitled Synthesis of Gona-3,5-dienes, filed Apr. 7, 1966 by Gordon Alan Hughes and Herchel Smith.

In accord with the present invention the 13-alkyl-l7- hydroxy-3-oxogona-4,6-diene-l7a-propionic acid, 'y-lactones (A) of this invention are utilized as intermediates in the preparation of the 13-a1kyl-17-hydroxy-7a-mercapto-3-oxogon-4-ene-l7a-propionic acid, 'y-lactone, alkylates (B) of this invention, which have been found to possess interesting pharmaceutical properties which render them useful as synthetic medicinals. More particularly, these compounds, in standard pharmacological tests have exhibited utility as anti-diuretic agents.

When the compounds of this invention are employed as anti-diuretic agents, they may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk sugar, certain types of clay and so forth. They may be administered sublingually in the form of troches or lozenges in which the active ingredient is mixed with sugar and corn syrups, flavoring agents and dyes; and then dehydrated sufliciently to make it suitable for pressing into a solid form. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parenterally, that is intramuscularly, intravenously or subcutaneously. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parentefally, In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects and preferably at a level that is in the range of from about 1 mg. to about 200 mg. per day, although as aforementioned variations will occur. However, a dosage level that is in the range of from about 5 mg. to about 50 mg. per day is most desirably employed in order to achieve effective results.

The following examples are given by way of illustration and are not to be construed as limitations of this invention, many variations of which are possible without departing from the scope and spirit thereof.

EXAMPLE I XE; 5.64, 5.70, 6.0, 6.13;; REEF 283 me (6 14,340)

Analysis.-Calcd for C H O C, 74.97; H, 8.42. Found: C, 74.48; H, 8.42.

The above prepared 13-ethyl-3, 17-dihydroxygona-3,5- diene-17a-propionic acid, 'y-lactone, acetate (5.5 g.) in acetone (473 ml.), pyridine (3.2 ml.), sodium acetate (15 g.), water (150 ml.) and acetic acid (15 ml.) is chilled to 0 C. and N-bromosuccinimide (2.75 g.) is added to the mixture. The mixture is then stirred at 0 C. for two hours, poured into brine and extracted with ether. Thereafter, most of the ether is removed while the solution temperature is maintained below 15 C. and calcium carbonate (16.5 g.) and dimethylformamide (385 ml.) are added. The ether is then boiled off and the reaction mixture is refluxed for two hours. Filtration, washing of the cake with ether, pouring into brine and extraction with ether followed by washing, drying and evaporating the ether layer yields the crude product. Recrystallization from ethyl acetate yields 13-ethyl-l7-hydroxy-3-oxogona- 4,6-diene-l7a-propionic acid, 'y-lactone (2.25 g.) M.P. 216-218 C.,

with 5.67, 6.06, 6.20, 6.34 1; x532? 284 m (6 21,141)

Analysis.Calcd. for C H O C, 77.61; H, 8.29. Found: C, 77.38; H, 8.29.

The 13 ethyl 17 hydroxy 3 oxogona 4,6 -diene 17e-propionic acid, -lactone (2.25 g.) prepared above is then refluxed in thiolacetic acid (5 ml.) for two hours. Subsequently, the excess acid is removed under reduced pressure, the residue triturated with cold ether and filtered. The collected solid is triturated with boiling ethyl acetate, the suspension chilled and filtered to yield 13 ethyl 17 hydroxy 7a mercapto 3 oxogon 4 ene 17oz propionic acid, 'y-lactone, acetate (1.55 g.), M.P. 218-220" C.,

REE; 5.67, 5.92, 6.0a; A223? 240 mp. (6 19,400)

Analysis.Calcd for C H O S: C, 69.21; H, 7.74. Found: C, 69.17; H, 7.44.

EXAMPLE II 13 butyl 17 hydroxy 3 oxogon 4 ene 17a propionic acid, 'y-lactone (10.0 :g.) is refluxed for four hours with isopropenyl acetate ml.) and p-toluenesulfonic acid (2.0 g.) Thereafter, the liquids are removed under vacuum, the residue triturated with cold ethanol and filtered to yield 13 butyl 3,17 dihydroxygona 3,5 diene-17 a-propionic acid, -lactone, acetate.

The above prepared compound in acetone (950 ml.), pyridine (6.5 ml.), sodium acetate (30 g.), 'water (300 m1.) and acetic acid (30 g.) is cooled to 5 C. and then admixed with N- bromosuccinimide (5.5 g.) The reaction mixture is stirred at 5 C. for four hours, then poured into a saturated potassium chloride solution and extracted with chloroform. Subsequently, most of the chloroform is removed from the combined extracts (at temperatures below C.) and the residue is admixed with calcium carbonate (33 g.) and dimethylformamide (770 ml.). The remaining chloroform is removed by evaporation and the reaction mixture is refluxed for three hours. The mixture is then filtered, washed with ether, poured in brine and extracted with ether. The combined ether extracts are then evaporated to dryness and the residue recrystallized from ethyl acetate to yield 13 butyl l7 hydroxy 3 oxogona-4,6-diene-17a-propionic acid, 'y-lactone.

The aforesaid 13 bntyl 17 hydroxy 3 oxogona 4,6 diene 17a propionic acid, -lactone is then refluxed with thiolpropionic acid (5 ml.) for four hours. Thereafter, the excess acid is removed under vacuum, the residue triturated with cold ether and filtered. The resulting solid is triturated with boiling ethyl acetate, and the suspension chilled and filtered to yield 13-butyl-17-hydroxy- 7a mercapto 3 oxogon 4 ene 17a propionic acid, 'y-lactone, propionate.

EXAMPLE III 13 hexyl 17 hydroxy 3 oxogon 4 ene 17oz propionic acid, 'y-lactone (15.0 g.) is refluxed for three hours with isopropenyl acetate (195 ml.) and sulfuric acid (9 ml.). Thereafter, the liquids are removed under reduced pressure, the residue triturated with propanol and filtered to yield 13 hexyl 3,17 dihydroxy 3 oxogon 3,5 diene-l7a-propionic acid, -lactone, acetate.

The above prepared compound in acetone (1420 ml.), pyridine (9.6 ml.), sodium acetate (45 g.), water (450 m1.) and acetic acid (45 g.) is chilled to 0 C. and N- bromosuccinimide (8.25 g.) is added thereto. The mixture is stirred at 0 C. for three hours, poured into brine and extracted with ether. Thereafter, most of the ether is removed, at temperatures below 10 C., and calcium carbonate (50 :g.) and dimethylformamide (1150 ml.) are added. The ether is removed by boiling and the reaction mixture is refluxed for three hours. The mixture is then filtered, washed with ether, poured into brine and extracted with ether. The combined extracts are washed, dried and then evaporated to dryness, the residue is recrystallized from ethyl acetate to yield 13 hexyl 17 hydroxy 3 oxogona 4,6 diene 17a propionic acid, 'y-lactone.

The 13 hexyl 17 hydroxy 3 oxogona 4,6 diene l7a-propionic acid, -lactone prepared above is then refluxed in thiolbutyric acid (15 ml.) for three hours. Thereafter, the excess acid is removed under vacuum, the residue triturated with cold hexane and filtered. The solid is triturated with warm ethyl acetate, chilled and filtered to obtain 13 hexyl l7 hydroxy 7a mercapto 3 oxogona-4-ene-17a-propionic acid, 'y-lactone, butyrate.

EXAMPLE IV 17 hydroxy 3 oxogon 4 ene 13 propyl 17a propionic acid, 'y-lactone (5.0 g.) is refluxed for two hours with propionic anhydride (90 ml.) and p-toluenesulfonic acid (1 g.). Thereafter, the liquids are removed under vacuum, the residue triturated with cold methanol and filtered to yield 3,17 dihydroxygona 3,5 diene 13 propyl-17 m-PX'OPiOHlC acid, -lactone, propionate.

The above prepared 3,17 dihydroxygona-3,5-diene-13- propyl-17a-propionic acid, -lactone, propionate in acetone (473 ml.), pyridine (3.2 ml.) sodium acetate (15 g.), water (150 ml.) and acetic acid (15 ml.) is chilled to 0 C. and N-bromosuccinimide (2.75 g.) is added thereto. The mixture is stirred at 0 C. for two hours, poured into brine and extracted with ether. Most of the ether is removed not allowing the solution above 15 C. and calcium carbonate (16.5 g.) and dimethylformamide (385 ml.) are added. The ether is boiled 01f and the reaction mixture is refluxed for two hours. Filtration, washing of the cake with ether, pouring into brine and extraction with ether followed by washing, drying and evaporating the ether layer gives the crude product. Recrystallization from ethyl acetate provides 17-hydroxy 3 oxogona-4,6- diene-l3-pr0pyl-17a-propionic acid, 'y-lactone.

The above prepared compound is refluxed in thiolvaleric acid (5 ml.) for two hours. The excess acid is removed under reduced pressure, the residue triturated with ice cold ether and filtered. The solid is triturated with boiling ethyl acetate, the suspension chilled and filtered to obtain 17 hydroxy 7oz mercapto 3 oxogona 4 ene 13 propyl-lh-propionic acid, 'y-lactone, valerate.

What is claimed is:

1. An anti-diuretic compound selected from the group consisting of those having the formula:

wherein R is alkyl containing from two to six carbon atoms and R is lower alkyl.

2. As an anti-diuretic compound, l3-ethyl- 17-hydroxyc mercapto 3 oxogon 4 ene 17a propionic acid, 'y-lactone, acetate.

3. As an anti-diuretic compound, 13-buty1-17-hydroxy- 7oz mercapto 3 oxogon 4 ene 17oz propionic acid, 'y-lactone, propionate.

4. As an anti-diuretic compound, 13-hexyl-l7-hydroxy- 7 a mercapto 3 oxogona 4 ene 17 a propionic acid, -lactone, butyrate.

5. As an anti-diuretic compound, 17 hydroxy 7a mercapto 3 oxogona 4 ene 13 propyl 17a -propionic acid, 'y-lactone, valerate.

References Cited UNITED STATES PATENTS 3,013,012 12/1961 Cella et al 260-23957 OTHER REFERENCES Smith et al.: Experientia, August 1963, pp. 394-396.

LEWIS GOTIS, Primary Examiner. ETHEL G. LOVE, Assistant Examiner.

US. Cl. X.R. 260-999 

